DESCRIPTION OF THE PPG (provided by the applicant): MRSA is a leading cause of severe invasive infection and mortality. This has become urgent with the introduction of vancomycin resistance from VRE (leading causes of multidrug resistant hospital infection). The PPG theme is New approaches for combating MRSA and VRE infection based on novel compound screens and an understanding of development, physiology, and spread of antibiotic resistance. The PPG aims to shift treatment paradigms by providing to development pipelines as deliverables, 10 validated compounds for treating these infections ~ while simultaneously making significant advances to the underlying science. The interdisciplinary team will take an innovative academic approach that involves creative new screens and information-based compound identification, coupled with an advanced understanding of the molecular biology of antibiotic resistance and its transmission. This collaborative partnership, with expertise in high throughput screening/follow up chemistry, biochemistry, molecular biology, molecular genetics, molecular pathogenesis, and clinical microbiology, brings the perspectives and assets of institutions spanning Harvard University- MGH, HMS, Harvard College, and Mass. Eye and Ear Infirmary - to bear. All Project Leaders are leaders in their respective fields, comprising a team of unusual scientific breadth and accomplishment, and administrative experience. Synergy allowed significant advances to be made in the first year. An initial lead and a second, optimized structure for inhibiting MRSA WTA synthesis were generated in the Walker project. Working with the Gilmore group, these compounds were shown to be effective in mammalian tissues, to be non-toxic, and to have low MICs for clinical isolates of MSSA and MRSA; moreover, WTA deficient strains were extremely sensitive to Congo Red and other azo compounds, leading to the design of new screens for the proposed period. Collaborative work with the Mylonakis/Ausubel and Hooper groups showed that WTA defective S. aureus could be successfully treated with b-lactams in C. elegans and murine models respectively. This one line of investigation ran through all groups, and the 2nd generation WTA inhibitor is now advancing through the NIH preclinical development pipeline. RELEVANCE: Three projects take independent, innovative, and state-of-the-art approaches for identifying lead compounds for treating MRSA, VRE and VRSA infection, and expanding the knowledge base that underlies their activity. Two additional projects test these compounds in vitro and in vivo, and determine their relationship to antibiotic resistance and resistance transmission. One compound already has been validated, and the goal of this program is to deliver 10 more along with advancing the attendant science